1. Field of Invention
This invention relates to novel compositions of matter for topical application to humans and methods for providing therefrom a predetermined dosage of nitroglycerin. The novel compositions comprise stabilized nitroglycerin in a form adapted for the slow and gradual release thereof so as to provide a sustained level of the drug in the blood of the patient.
2. Description of the Prior Art
Nitroglycerin (glyceryl trinitrate) has been in use for many years as a coronary vasodilator and is especially useful in the treatment of cardiac diseases such as angina pectoris. Nitroglycerin is generally used in the form of sublingual tablets or capsules, composite gradual release tablets, ointments and patches.
Nitroglycerin is rapidly absorbed through mucous membranes and the effect of sublingual tablets starts some 3 minutes after taking the medication and lasts for about 30 minutes. The duration of the effect of tablets taken internally is of the same order of magnitude.
Notwithstanding its efficacy, the high volatility and mobility of the nitroglycerin leads to a loss of the drug to the environment during storage and use. Thus, when tablets containing nitroglycerin and an excipient such as lactose are exposed to the atmosphere in a semienclosed or open container, the loss of nitroglycerin results in a change in the nitroglycerin content of the tablets. Further, the mobility of nitroglycerin is manifested by the migration of the drug from one tablet to another when such tablets are in contact with each other in a closed container over an extended period of time.
The stabilization of nitroglycerin tablets against losses to the atmosphere by volatilization and tablet-to-tablet migration has been accomplished by the incorporation of water-soluble polyvinylpyrrolidone into the mixture of components used in the preparation of the tablets. Thus, Fung et al. in Journal of Pharmaceutical Sciences, 63, 1810 (1974), disclosed that the addition of polyvinylpyrrolidone to a tablet containing nitroglycerin and lactose, retarded the rate of evaporation of the nitroglycerin from the tablet. However, the solid phase stabilization did not affect the availability of the nitroglycerin in an aqueous environment because of the preferential solvation and the rapid solubilization of the vinylpyrrolidone homopolymer in water.
German DOS 2,301,664 and British Pat. No. 1,427,881 disclose the prolongation of the storage stability of nitroglycerin by the addition of polyvinylpyrrolidone. U.S. Pat. No. 4,091,091 describes the stabilization of nitroglycerin against tablet-to-tablet migration by the incorporation of water-soluble polyvinylpyrrolidone in the mixture of a water-soluble excipient and nitroglycerin, while retaining the rapid solubility of the tablet in the mouth.
The release of nitroglycerin as a result of the water-solubility of vinylpyrrolidone homopolymer or copolymers has also been utilized in an antianginal film or plate. Thus, British Patent Application 2 021610 A discloses that a thin film containing nitroglycerin, a water-soluble homopolymer or copolymer or acrylamide and/or vinylpyrrolidone and, optionally a dispersed solid fat, is applied to a site in the mouth and releases the medicament at a rate which is dependent upon the rate of solution of the polymer.
Nitroglycerin is rapidly absorbed through unbroken skin as well as through mucous membranes in the mouth. U.S. Pat. No. 3,742,951 discloses a medical bandage or patch comprising a backing member, a reservoir containing nitroglycerin and a pressure sensitive adhesive coating. The reservoir is in the form of microcapsules or matrix layers which are polymeric, preferably silicone rubbers, and permeable to nitroglycerin. The rate of release of nitroglycerin is controlled by the permeability of the polymer in the microcapsule wall or matrix layer. U.S. Pat. No. 4,336,243 discloses a transdermal delivery system for administration of nitroglycerin wherein the latter is present in microsealed compartments in a polymer which is insoluble in body fluids and through which the nitroglycerin can pass at a controlled rate. The polymer, preferably a silicone rubber, contains a hydrophilic solvent such as polyethylene glycol and a hydrophobic solvent such as mineral oil which partition and enhance the diffusion of nitroglycerin throughout the matrix. U.S. Pat. No. 4,291,015 discloses a water-containing polymeric matrix for the transdermal delivery of nitroglycerin. The matrix contains water and a polar plasticizer such as glycerin, with small amounts of a hydroxyl-containing polymer such as polyvinyl alcohol and a water-soluble polymer such as polyvinylpyrrolidone. The polymers provide retention of the shape of the water-containing matrix.
The absorption of nitroglycerin through unbroken skin makes possible topical application in the form of ointments. Nitroglycerin ointments based on lanolin, vasoline or similar hydrophobic and practically water-insoluble bases are effective for about 3 to 4 hours. However, when these ointments are applied to the skin, part of the nitroglycerin is lost by volatilization and the base is rapidly absorbed into the skin.
The present invention is directed towards improvements in stabilized nitroglycerin compositions which upon topical application will have reduced volatilization of the nitroglycerin, slow release of the drug upon contact with moisture and provide a slow and sustained release of the nitroglycerin so as to maintain the desired sustained level of the drug in the blood of the patient. This is accomplished by the incorporation of water-insoluble vinylpyrrolidone homopolymer or copolymers.
The use of water-soluble polyvinylpyrrolidone in conjunction with medicaments other than nitroglycerin has been disclosed in a number of patents. Thus, U.S. Pat. No. 3,972,995 discloses a buccal dosage form in which the water-soluble homopolymer functions as a binder in an adhesive layer. U.S. Pat. No. 3,214,338 discloses a topical ointment in which the water-soluble homopolymer is added to an emulsifiable polyvinyl acetate powder. U.S. Pat. No. 3,803,300 discloses a film-forming ointment containing water-soluble vinylpyrrolidone homopolymer and copolymers. U.S. Pat. No. 3,287,222 discloses the use of the homopolymer as a water-soluble plasticizer in an impregnating solution for a synthetic fiber medical dressing. U.S. Pat. No. 4,210,633 discloses a water-soluble medicated film containing the water-soluble homopolymer. U.S. Pat. No. 3,608,070 discloses a surgical dressing which is an ointment containing a vinylpyrrolidone copolymer, a thixotropic agent, a water-soluble plasticizer and a solvent such as aqueous ethanol. The film formed on drying the ointment is readily soluble in water. U.S. Pat. No. 2,776,924 discloses the use of water-soluble polyvinylpyrroidone to inhibit adverse reactions from therapeutic agents in topical application.
In these prior art disclosures with medicaments other than nitroglycerin, vinylpyrrolidone polymers are used because of their film-forming ability and/or water solubility. The rapid solubilization of the polymer results in rapid release of the medicament.
The prior art discloses that the use of water-insoluble, crosslinked polyvinylpyrrolidone also promotes the rapid release of medicament. Thus, British Pat. No. 1,380,171 discloses the use of crosslinked, water-insoluble polyvinylpyrrolidone in medicinal tablets containing a drug, to promote rapid disintegration of the tablet in aqueous fluids and increase the availability of the drug. Examples are provided which illustrate that the presence of water-insoluble polyvinylpyrrolidone results in more rapid disintegration and release of the drug as compared with the water-soluble polymer. German Patent Application 2,634,004 discloses the use of crosslinked, insoluble polyvinylpyrrolidone as a carrier material for poorly soluble medicaments in order to accelerate the release thereof when administered orally. German Patent Application 1,467,792 discloses the use of crosslinked polyvinylpyrrolidone as a disintegrating agent to increase the rate of disintegration of a tablet and to promote the extremely rapid release of the drug therein in the digestive tract.
In a non-pharmaceutical application, British Pat. No. 1,090,184 discloses the use of polyvinylpyrrolidone as well as numerous other polymers soluble in nitroglycerin, including polymethyl methacrylate, polyvinyl acetate and non-hardened phenol-formaldehyde resin, as gelatinizing additives in the production of explosive compositions.